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bioRxiv · 10.1101/2021.07.01.450417

Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells

Shi, Y.·Dolan, M.·Mastri, M.·Hill, J. W.·Dommer, A.·Benzekry, S.·Eng, K.·Ebos, J. M. L.
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Abstract

BackgroundInterferon (IFN) pathway activation in tumors can have dual, sometimes opposing, influences on immune responses. Therapeutic inhibition of programmed cell death ligand (PD-L1) - a treatment that reverses PD-1-mediated suppression of tumor-killing T-cells - is linked to alterations in IFN signaling; however, less is known about the role of IFNs after treatment resistance. Since IFN-regulated intracellular signaling can control extracellular secretory programs in tumors to modulate immunity, we examined the consequences of PD-L1 blockade on IFN-related secretory changes in preclinical models of acquired resistance. MethodsTherapy-resistant cell variants were derived from orthotopically grown mouse tumors initially sensitive or insensitive to PD-L1 antibody treatment. Cells representing acquired resistance were analyzed for changes to IFN-regulated secretory machinery that could impact tumor progression. ResultsWe identified a PD-L1 treatment-induced secretome (PTIS) that was enriched for several IFN-stimulated genes (ISGs) and significantly enhanced when stimulated by type I IFNs (IFN or IFN{beta}). Secretory changes were specific to treatment-sensitive tumor models and found to suppress activation of T cells ex vivo while diminishing tumor cell cytotoxicity, revealing a tumor-intrinsic treatment adaptation with potentially broad tumor-extrinsic effects. When reimplanted in vivo, resistant tumor growth was slowed by the blockade of individual secreted PTIS components (such as IL6) and stopped altogether by a more generalized disruption of type I IFN signaling. In vitro, genetic or therapeutic methods to target PD-L1 could only partially recapitulate the IFN-enhanced PTIS phenotype, showing that in vivo-based systems with intact tumor:immune cell interactions are needed to faithfully mimic acquired resistance as it occurs in patients. ConclusionsThese results suggest that prolonged in vivo PD-L1 inhibition can rewire type I IFN signaling to drive secretory programs that help protect tumors from immune cell attack and represent a targetable vulnerability to overcome acquired resistance in patients.

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Shi, Y., Dolan, M., Mastri, M., Hill, J. W., Dommer, A., Benzekry, S., Eng, K., Ebos, J. M. L.. 2021-07-01. Acquired resistance to PD-L1 inhibition is associated with an enhanced type I IFN-stimulated secretory program in tumor cells. https://doi.org/10.1101/2021.07.01.450417

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